ABSTRACT. In recent years, advances in sequencing technologies and simultaneous improvements in the ancient DNA field have revolutionized our understanding of the evolutionary history of pathogens. Most notably, targeted DNA enrichment techniques have allowed to identify the causative agents of historic pandemics and to reconstruct their genomes, resulting in direct insights into the history and origins of these pathogens. We are now able to trace back the evolutionary and population dynamic processes of bacterial pathogens as well as their adaption mechanisms to various hosts throughout historical times presumed to be out of reach by prior methods. Here, we will use two examples, Mycobacterium leprae and Treponema pallidum to showcase the potential and variety of ancient pathogen studies and to discuss challenges and benefits arising from the current techniques for ancient pathogen DNA retrieval and analysis.

ABSTRACT. Natural bacterial communities in the environment and in infections are typically diverse, yet we know little about the factors that determine interspecies interactions. Here, we apply concepts from ecological theory to understand interaction patterns between the two opportunistic human pathogens Pseudomonas aeruginosa and Staphyloccocus aureus, which often co-occur in polymicrobial infections. We focus on three ecological parameters potentially influencing bacterial communities. First, we predict that the spatial structure of the environment helps to physically segregate species from one another, thereby weakening competition and promoting co-existence. Second, we examine whether the genetic background of strains plays a role in competition. Third, we assess whether frequency-dependent dynamics occur. We tested our predictions by conducting competition assays between two P. aeruginosa and three S. aureus strains across three levels of spatial structures and three different starting frequencies. We found that increased spatial structure did not foster co-existence, but shifted the competitive dynamics in favor of P. aeruginosa. We further observed that the genetic background of both P. aeruginosa and S. aureus had a strong influence on competition outcomes, whereby both species can end up as winners depending on strain pair combinations. Finally, we found evidence for positive frequency-dependent selection showing that P. aeruginosa strains cannot invade populations when rare, but dominate when initially occurring at high frequency. Our findings have three potentially important implications for polymicrobial infections. First, interactions and pathogen dominance in infections are determined by strain background and might thus vary from patient to patient. Second, frequency-dependent selection might limit the opportunity of rare pathogens to invade an established infection. Third, a change in the physical structure at the infection site, possibly induced by treatment, might alter competitive dynamics. Altogether, our study highlights that ecological and evolutionary principles can help to understand polymicrobial infections.

ABSTRACT. The emergence and re-emergence of pathogens remains a major public health concern. Unfortunately, when and where pathogens will (re-)emerge is notoriously difficult to predict, as the erratic nature of those events is reinforced by the stochastic nature of pathogen evolution during the early phase of an epidemic. For instance, mutations allowing pathogens to escape host resistance may boost pathogen spread and promote emergence. Yet, the ecological factors that govern such evolutionary emergence remain elusive because of the lack of ecological realism of current theoretical frameworks and the difficulty of experimentally testing their predictions. Here, we develop a theoretical model to explore the effects of the heterogeneity of the host population on the probability of pathogen emergence, with or without pathogen evolution. We show that evolutionary emergence and the spread of escape mutations in the pathogen population is more likely to occur when the host population contains an intermediate proportion of resistant hosts. We also show that the probability of pathogen emergence rapidly declines with the diversity of resistance in the host population. Crucially, we experimentally confirm these theoretical predictions using lytic bacteriophages infecting their bacterial hosts containing Clustered Regularly Interspaced Short Palindromic Repeat and CRISPR-associated (CRISPR-Cas) immune defenses as a model system. These results suggest effective strategies for cross-species spillover and for the management of emerging infectious diseases.

ABSTRACT. Sepsis is a common, expensive, and often challenging diagnosis with the potential for high mortality and morbidity. Every year, approximately 1 million people in the United States are diagnosed with sepsis, with a mortality of 15-30% with similar statistics found in many other countries. However, accurately diagnosing and treating sepsis remains an elusive goal.

Sepsis, as defined by the 3rd International Consensus on Sepsis, is life-threatening organ dysfunction caused by a dysregulated host response to infection. On the surface, this definition does not seem to represent a particularly adaptive process; however, sepsis is a commonly encountered medical diagnosis. The high mortality rate of sepsis is canonically explained by the immune system causing self-harm disproportionate to the underlying infection. Evolutionary theory leads us to explain this paradox with one of these concepts: mismatch, tradeoff, constraint, or defense.

In order to further explore these questions, we performed a comprehensive chart review on 200 patients who received antibiotics in the emergency department of an academic community hospital prior to hospital admission. We performed data analysis in order to identify support for a mismatch, tradeoff, constraint, or defense explanation and applied a series of hypotheses in order to test these concepts. We compared various sepsis criteria and lab values among cohorts of patients based on comorbidities, infection status, and clinical outcomes. Further, in order to better understand the nature of sepsis as opposed to other acute medical conditions, we compared patients who were found to have an infection with those in whom infection was ruled out during their hospitalization. We also compared those with infection who presented with sepsis with those with an infection that did not present with sepsis. Using these tools, we hope to further the understanding of the pathology and evolution of the sepsis response to infection.

ABSTRACT. Social groups can fight disease collectively. Thereby, the individual defenses of each group member are complemented by jointly performed hygiene and mutual sanitary care. Social interactions can hence interfere with the course of disease in individual group members and transmission to group members. Ants and other social insects show particularly sophisticated cooperative disease defenses that protect the whole colony. We observed the social interactions of healthy ants and their pathogen-contaminated colony members and find that both, contaminated and healthy individuals, change their behavioral profiles and spatial preferences upon pathogen entry to the colony. This alters the colony-wide interaction network and reduces disease spread through the colony. We further tested whether the hygiene measures of the ants – pathogen removal by grooming and disinfection by antimicrobial compounds – exerts a strong selection pressure on their pathogens. To address this, we let fungal pathogens of ants evolve in the presence or absence of social defenses, that is, (i) in groups of ants or (ii) in single ants. We found that pathogens adapting to groups of ants showed higher production of new infectious stages and elicited altered sanitary care by the ants than pathogens that had evolved only with single ants. Our work reveals that the collective defenses of social insects have strong impact on disease transmission and pathogen evolution.

ABSTRACT. Leprosy is one of the oldest known diseases in human history with possible osteoarchaeological cases dating back till the Late Copper Age (3,650 BC) in Hungary. Molecular biological approaches, such as ancient DNA research focussing on the causative agent, Mycobacterium leprae, can greatly contribute towards understanding the evolutionary history of the disease. Previous genetic studies of ancient M. leprae genomes in comparison with modern strains have identified genomic continuity over the last 1,000 years and the existence of at least four lineages in medieval Europe. However, the ancient genomes published so far concentrate on certain regions of Europe which probably do not reflect the diversity of other regions. Here, we address this issue through the genetic examination of several medieval and post-medieval samples from so far unstudied regions. Up to now, three new ancient M. leprae genomes have been already reconstructed: two medieval genomes from Portugal (1,340 ± 48 AD) and Norway (1,328 ± 60 AD) and a genome from Russia dated to the 19th-20th century. Ongoing analysis is focuses on the reconstruction of additional ancient leprosy genomes in order to more fully capture the diversity of the ancient M. leprae strains in Europe. The phylogenetic analysis of the reconstructed genomes, including previously published modern and ancient genomes, reveals that the genomes from Portugal and Norway fall on branch 3. The genome from Russia is located on branch 2F and clusters with modern Ethiopian strains. Overall, our results contribute to a better understanding of the past diversity of leprosy in Europe by adding genomic data from so far unstudied regions.

ABSTRACT. As one of the oldest known human diseases, Hansen’s disease or leprosy has left humankind a legacy of fear and social stigmatization, and it remains a public health concern in many places with almost 211,000 new cases worldwide in 2017, including 4084 in the Western Pacific, according to the World Health Organization. Most human leprosy cases are caused by Mycobacterium leprae, but a small number case are now known to be caused by M. lepromatosis, which is a sister taxon of M. leprae. At present, the pattern of genomic variation in leprosy strains around the world is not well understood, since there are relatively few genome sequences available for analysis. To address this, as well as to begin to investigate patterns of pathogen exchange across Polynesia, we extracted DNA from eight formalin-fixed paraffin embedded biopsy blocks dating to 2011-2015. We used targeted-capture and sequencing on the Illumina HighSeq 2500 at 2x100 to sequence the genome, obtaining a depth of coverage ranging from 2.5 to 95x. Our preliminary analyses indicate that these strains belong to basal lineages within the M. leprae phylogeny, specifically falling in branches 0 and 5. Further comparative and phylogenetic analyses of these strains will help to clarify the geographic patterning and evolutionary history of leprosy.

ABSTRACT. Sex differences exist across a range of human diseases, that to date have been understudied and largely unexplained. For example, females in industrialized populations exhibit a higher prevalence of most autoimmune diseases than do males. By contrast, females have a lower risk of developing cancer, with nearly all non-reproductive cancers showing a higher incidence in males. Here we present the Pregnancy Compensation Hypothesis (PCH), which explains both the proximate and ultimate (evolutionary) mechanisms responsible for sexual dimorphism observed in human disease, as mediated by selection on the immune system due to pregnancy and placentation. We propose that because evolution has shaped the human immune system differently in males and females, under industrialized conditions that differ from the ancestral state, we expect sex differences in diseases to be more pronounced in urban, industrialized contexts.

Under the PCH, we propose that the evolution of eutherian placentation exerted significant sex-specific selection on immune function to tolerate fetal antigens while still defending the pregnant individual against parasites and pathogens. We theorize that this process is regulated proximately via hormones and mediated genetically by dosage on the sex chromosomes, and that today, the mismatch between an ancestral environment (being pregnant or lactating for the majority of adult reproductive years) and urban industrial environment (where common contraceptive use results in reduced pregnancies) interacts with this evolved compensatory immune regulation and results in the observed sex differences in disease risk. Finally, a sedentary lifestyle that affects reproductive hormone levels exacerbates these differences.

Here we focus on two disease classes with documented immune components that show sex differences in incidence and treatment: autoimmune diseases and cancer. We unpack the interrelated components of the PCH related to shifting reproductive states, parasite loads, and energetic availability, which are particularly relevant for sex differences in human disease.

ABSTRACT. It is becoming apparent that changes in human exposures and behaviors are shaping future health adversities. The availability of big data and multi-omics technologies are now providing deeper insights into human variation and disease susceptibility. Using Singapore’s most deeply phenotyped and omics- profiled mother-offspring cohort, GUSTO (Growing Up in Singapore Towards healthy Outcomes), I will share how this study has helped to: (i) comprehensively map the molecular and phenotypic variability in Asians in both pediatric and adult populations, (ii) how this variability is linked with non-communicable diseases that are plaguing global health and economy, and (iii) how we can use these data for developing precision healthcare for future generations.

ABSTRACT. Cesarean Section (CS) rate is high in developed and in developing countries. The optimal CS rate according to the WHO is around 10-15%. In Brazil, however, nearly 55% of babies are delivered by CS, suggesting a biased health system towards surgical birth. Delivery by CS has been associated with later life health outcomes. A recent meta-analysis of 28 studies found that children delivered by CS had a 34% greater risk [95%CI 1.18-1.51] of being obese during childhood and adolescence. Another meta-analysis, which included broader age groups, found that the association was present within different age strata. Similar findings were reported when highly different socio-economic settings were compared. Studies have also demonstrated links between delivery by CS and adult chronic diseases such as asthma and type I diabetes. We followed up 2020 individuals from birth to 25 years of age. CS was significantly associated with higher hypertension rates when compared with vaginal delivery (11.7 vs 7.7%, respectively). The risk for hypertension after adjusting for confounders was OR=1.49 (1.07-2.06). Evolutionary medicine allows us to look at this fact through a different point of view when compared to traditional clinical reasoning. Thus, we sought to analyze this situation using a clinical reasoning based on evolutionary medicine in an attempt to understand what are the long-term effects of CS. For that, a review of the literature on the subject was made and a theoretical model was developed that could explain this association. Given the burden of non communicable diseases, we highlight the importance of public incentives to promote vaginal birth in countries like ours.

ABSTRACT. Microbial communities inhabiting terrestrial and aquatic ecosystems have long been studied. With the onset of metagenomics, the degree of diversity and abundance of these communities has become apparent, even on a global scale. In contrast, the atmosphere, with its sizeable planetary volume, has largely been neglected as a habitat for microbial communities, despite providing means of transport with an intercontinental range. We have studied the occurrence of airborne microbial organisms in the tropical climate of Singapore and found robust and persistent assemblages, both on intra-day and a month-to-month time scales. Bacteria and fungi were the major constituents of the air microbiome, in addition to DNA derived from plants and insects. Besides conducting in-depth metagenomics studies that identified the diversity and abundance of airborne organisms, we have sequenced and assembled “100 genomes from air” using single-molecule sequencing (SMRT). These genome data from various indoor and outdoor settings, together with organismal and habitat information, are now enabling investigations of the impact of air environments on respiratory cohorts.

ABSTRACT. The inextricable linkage of human and animal health has been increasingly recognized in the past decades. However, human and veterinary medicine are often working so much in separation that human and animal health is affected. We define One Health (OH) as the added value in terms of human and animal health benefits, financial and other resource savings and improved environmental services compared to the two medicines working in separation. An integrated assessment of human and animal health requires methods capable of assessing effects on the animal – human interface. For example livestock mass vaccination against brucellosis is not profitable for the public health sector alone but becomes largely profitable from a societal perspective including all involved sectors. Dog rabies control in Africa by mass vaccination of dogs becomes less costly than human post-exposure prophylaxis alone after ten years. Other examples are provided from health services, integrated antimicrobial resistance surveillance and joint laboratory infrastructure. Conceptually OH is embedded in broader ecosystem approaches to health which can also be called health in social-ecological systems or health in human-environment systems which is also important for non-communicable diseases. In this way human and animal health improvements will be developed while considering social dynamics and sustained ecosystem services.

ABSTRACT. The current urbanization is one of the biggest environmental challenges and has led to a worldwide increasing number of wildlife species to conquer this new type of biotope. This results in novel communities of species that share a habitat that have mainly been selected based on their synantropism. Selection based on habitat parameters such as climate, diet, density is ongoing, while new species experience urbanization. Whilst multiple studies investigate the impact of abiotic parameters, the evolution of infectious agents in urban wildlife is widely unknown. Here, we describe what impact urban habitats can have on pathogens, their vectors, and hosts. Special attention is given to aspects linked to novel opportunities of cross species transmission, the effect of dim light at night and pollution. We propose to develop a network based on the One Health approach to study the ongoing evolution of infectious agents in urban wildlife, to compare the epidemiology with the species in the original habitat and to assess the impact of infectious agents with respect to conservation issues as well as possible public health concerns.

ABSTRACT. All physiology, including vulnerability to disease, is the product of evolved adaptations. Exploring this vulnerability across the animal kingdom leads to: 1) an expanded understanding of disease causation 2) accelerated biomedical innovation and 3) identification of natural animal models of disease resistance. This lecture will explore methodology for developing comparative insights, generating novel hypotheses and conceiving of bio-inspired investigation.

ABSTRACT. The One Health movement is based upon the recognition that human health is connected to animal health and the environment. While this movement is a good first step in raising awareness of the close connections between human and animal health, the focus needs to be expanded beyond the initial emphasis on animal diseases as threats to human health. An evolutionary perspective is critical for developing an integrated view of what is driving disease susceptibilities across species and how such susceptibilities in one species can inform those impacting another. In particular, an evolutionary perspective emphasizes how adaptations to the environment through modifications of common genetic pathways have resulted in species variations in susceptibility to disease. For example, the genes regulating calcium and phosphorus homeostasis evolved in fish. Expression and function of these mediators was repurposed during subsequent adaptation to various land environments, and it is these modifications that determine species difference in susceptibility to metabolic bone diseases (i.e.: rickets). An evolutionary based One Health perspective also removes two major obstacles to the full utilization of animal models: 1) the misconception that disease in animals is the same as in humans (i.e.: a mouse is a human), and 2) only animal models that exactly reproduce human disease are useful. No animal model perfectly replicates human disease phenotypes, however without evolution to provide a context to assess these species differences, they are often ignored. This also means that the basis for the differences between human and animal disease phenotypes, which have potentially important therapeutic implications, are generally not studied. Finally a cross-disciplinary evolution based approach to understanding the environmental factors impacting human and animal disease facilities a much deeper understanding of how human modified environments affect both human and animal health.

ABSTRACT. What is a disease? Philosophers of medicine have investigated the term's meaning and locked themselves in a “conceptual straightjacket” (Hesslow 1993) by priorizing a consistent rendering of common usage. Instead, they can explore contemporary science for concepts and theories of natural disease phenomena. This paper sketches one such possibility, starting with the observation that most cases of disease come with age, whatever the specific disease. A focus on theories and models of aging in contemporary biogerontology, biodemography and evolutionary biology, should help consolidate a biological concept or even a biological model or theory of ‘age-related diseases’ in general. Even if this would not determine what is common to all the things that we call ‘diseases’, it would help form a relevant and conceptually challenging concept of a core phenomenon associated with most diseases in human populations. The challenge is first to put together 3 basic theoretical frameworks, namely, Gompertz-Makeham models of the incidence of death in populations (biodemography), Medawar-Williams model of aging in evolution (evolutionary biology) and a consistent picture of the biological ‘hallmarks’ of aging (Lopez-Otin, 2013). The resulting model of aging should then feature as an explanatory factor in the etiology of age-related diseases, i.e., the most prevalent and/or deadly in a population. The final goal would be a general model of aging as a common cause to many diseases that are generally studied separately, despite the fact that aging is their major risk factor.

Griffiths, Paul E. and John Matthewson (2018) The British Journal for the Philosophy of Science 69: 301–27. Hesslow, Germund (1993) Theoretical Medicine and Bioethics 14: 1-14. López-Otín, Carlos et al. (2013) Cell 153: 1194–1217. Matthewson, John and Paul E. Griffiths (2017) The Journal of Medicine and Philosophy 42: 447–66. Nesse, Randolph M. (2001) Medicine, Health Care and Philosophy 4: 37–46.

ABSTRACT. Griffiths & Matthewson (2016) defend the so-called ‘selected effects account’ of dysfunction as the best candidate for a naturalist account of disease. Their paper is a welcome and important contribution to a literature in which, amongst naturalist position, undue focus has rested on Christopher Boorse’s the Biostatistical account of dysfunction/disease. Griffiths & Matthewson up-to-date-with-current biology account does much to strengthen and improve a position that so far has suffered from being mainly defended by people insufficiently attuned to the details of (evolutionary) biology.

This paper examines whether Griffiths’ and Mattewson’s improved selected effect accounts can survive the following problem: in those cases where traits and effects have been affected by organisms’ development in ‘new’ environments, can the account state whether these traits are functional or dysfunctional, and therefore healthy or disordered. ? This question builds on a general tenet of developmental biology, which is that traits and their effects do not exist in but are the result of the environment in which an organism develops. Immunesystems, for example, develop in and are primed by the environment.

Griffiths and Matthewson’s account is meant to accommodate such developmental plasticity. Nonetheless I argue that it lacks the resources to accommodate disorders that in some sense are the result of our developing in non-ancestral environments. And since many disorders are likely to be the result – in one way or the other – of our developing in ‘new’ environments, this spells trouble for the selected effects account of disorder – even in its most sophisticated form. The trouble may be avoided by significant revision of our concept of medical disorder. But that – I argue – takes us too far from the central interests of medicine to serve it appropriately.

REFERENCES Griffiths & Matthewson (2018), Evolution, Dysfunction, and Disease: A Reappraisal, BJPS, 69: 301–327.

ABSTRACT. Since J.B.S Haldane’s essay Disease and Evolution (1949) it has been widely recognised that disease is an important and distinctive factor in evolution. But in contemporary philosophy of medicine it is widely believed that ‘disease’ is value-laden term: whether a phenotype is normal or pathological cannot be determined without making value judgments. These two ideas are prima facie inconsistent. In earlier work I have defended evolutionary approaches to defining disease (Matthewson and Griffiths 2017, Griffiths and Matthewson 2018). Within evolutionary medicine authors such as Nesse (2001) have argued that, although evolutionary theory does not straightforwardly define disease, any definition should be informed by our best theories of why mortality and morbidity exist and are distributed as they are. In this presentation I defend an objective, biological distinction between normal and pathological phenotypes and show that this distinction is needed within biology, independent of any application to medicine. This biological understanding of pathology does not map perfectly onto how normal and pathological are distinguished in medical practice, and it may be that a distinct, medical understanding of pathology is needed. Whether or not that is the case, I argue that the biological understanding of pathology should guide the medical understanding of pathology as that understanding evolves in response to new biomedical findings.

ABSTRACT. Cancer is a disease generated by somatic mutations and clonal selection of cell lineages but also by the rapid germline evolution of genes that predispose to cancer. Indeed, several genes associated with cancer, also known as cancer or driver genes, show evidence of positive selection during the evolution of species, which could promote cancer risk as a secondary effect. Taking advantage of a list of 574 cancer genes collected in Cancer Gene Census database, we evaluated ancient and recent selective pressures on cancer genes using comparative genomics and population genetics approaches. We measured the role of purifying and positive selection in mammals applying the dN/dS ratio, on the human lineage after splitting from chimpanzee estimating branch-specific dN/dS and Neutrality Index, and on human populations applying polymorphism-based selection statistics (iHS, Fst and Tajima´s D) on 1000 genomes project data. We evaluate the global selective pattern of cancer genes with respect to a background of the human coding genome, compare the selective pressures among different functional categories of cancer genes, and explore functional enrichment of cancer genes subjected to positive selection across the three levels. Our study will provide insights onto the origin of cancer and have important implications for understanding the links between evolutionary forces, positive selection on cancer genes and increased cancer risk.

ABSTRACT. Currently in Western societies solid malignancies represent one of the leading causes of death given the general decline in tissue structure and function associated with age. Ovarian cancer is the second most common gynecological cancer and the deadliest in absolute rates, with more than 280.000 new cases and 183.000 deaths predicted for 2020. Recent research based upon cost-effective whole genome data analysis has described ovarian cancer as a heterogeneous disease. Given it`s clinical features and pattern of carcinogenesis, ovarian cancer can be regarded as an evolutionary mismatch and can be used as a feasible model for studying tumor progression in solid malignancies. It shares with solid tumors features such as genetic diversity, clonal evolution, spatial and temporal genetic heterogeneity and development of drug resistance. There is growing evidence that dynamic interactions between ovarian cancer tumor cells and the host tumor microenvironment can actively influence therapeutic response. With this concept in mind, the multifaceted design of future basic, translational and clinical research and the development of predictive models for novel drug combinations represent a gateway towards tumor control in ovarian cancer and other malignancies.

ABSTRACT. Objective: Evolutionary anthropologists are unsure as to why selection would have ever favored menopause. Úbeda et al (2014) made a prediction about menopause symptoms: Consistent with the Grandmother Hypothesis, based on the intragenomic conflict, they find in populations with greater female-biased dispersal, women will experience a smaller degree of intragenomic conflict, shorter and less symptomatic peri-menopause and later menopause. There have been few studies testing it, and thus we propose to investigate the validity of the theory.

Methods: We use the Menopause symptoms Rating Scale (MRS) Questionnaire data from villages in Lugu lake and Zhaba in Sichuan province in China from 2 patrilocal populations and 2 matrilocal populations. The respondents' experience of the menopause was collected using the MRS that was developed by the Berlin Center, in which participants respond to statements (e.g. “I have hot flashes”, “I get heart palpitations”) on a 4-point Likert scale. For each individual, a ‘menopause symptoms score' (MSS) was created by summing the respondent's report of symptoms. This includes a total MSS, in additional to a vaso-motor MSS, a psychological MSS, and a physical MSS. Using these scores, we tested whether the residence pattern (matrilocal or patrilocal) of the individual is predictive of the severity of menopause symptoms. For the hypothesis to be supported, we would expect the matrilocal Mosuo and Zhaba to report worse symptoms than the patrilocal Han and the Yi.

Results: So far, according to the collected data, my conclusion is converse to the Úbeda‘s prediction. In my study, the primary results are: Whatever the female-biased dispersal is, the menopause timing is no difference; The Mosuo and the Zhaba females (smaller female-biased dispersal) have lower symptoms score than the Han and Yi (greater female-biased dispersal).

Conclusions: There is no evidence to support the intragenomic conflict hypothesis for the symptoms of peri-menopause.

ABSTRACT. The Polo-like kinase 4 (PLK4) is essential for centriole duplication, spindle assembly, and de novo centriole formation. Homozygous mutations in PLK4 lead to primary microcephaly. Here, we report a consanguineous, three generation family with 8 affected individuals, compound heterozygous for a novel missense variant of the PLK4 gene and a deletion of the other allele. The deletion was transferred to 14 of 16 offspring (P = 0.007). If individuals of other PLK4 families are included, there is a significant overrepresentation of affected probands (P<0.01). This also explains that among 24 informative offspring of heterozygote parents only a single individual was homozygous for the wild type allele. Thus, the deleted/mutated PLK4 alleles exhibit transmission ratio distortion (TRD) which cannot be explained by the known TRD mechanisms. Interestingly, a significant association has been reported between tripolar spindles and chaotic mosaic aneuploidies in cleavage stage embryos and a PLK4 linked haplotype (McCoy et al. Science 348:235-238, 2015). Under optimal conditions less than 30% of all fertilized human eggs result in a newborn. The vast majority of losses is due to meiotic and early mitotic aneuploidies. The highly error-prone mitotic divisions are controlled both by maternal gene products, including PLK4 and by paternal elements such as the centriol. Overexpression of PLK4 cause tripolar spindle formation. It is therefore assumed that PLK4 is normally overexpressed after fertilization, leading to mitotic aneuploidy and implantation failure to span the birth interval. Mutations/deletions of PLK4 could result in mitotic fidelity, more diploid embryos and hence preferential transmission of the deleted/mutated PLK4 alleles. Since the affected individuals have no children, this does not affect population fitness.

ABSTRACT. The rhythmic transcriptome is characterized by the set of genes that display rhythms in their mRNAs level which occur every 24 hours, i.e. which are nycthemeral. In baboon, 82% of protein-coding genes have been reported to be rhythmic in at least one tissue (Mure et al., 2018 Science 359: eaao0318). The nycthemeral rhythmicity of these transcripts can be driven by an internal oscillator clock, or by circadian behaviors such as food-intake, the light-dark cycle, sleep-wake behavior, or social activities. A common clock mechanism (transcription–translation feedback loop), driving the rhythmic expression of many genes, appears to be strongly conserved in evolution. This endogenous generated rhythm provides a time framework allowing organisms to anticipate environmental changes before they take place. Thus, many functions might benefit from this rhythmicity, and probably require it. Yet the evolution of the rhythmic transcriptome has not been studied so far, beyond core circadian genes. Here we have investigated the conservation of rhythmic orthologs, both as a starting point to study the evolution of rhythmicity, and to understand its functional role. Inter-species comparisons among vertebrates and among insects detect a high proportion of rhythmic orthologs with conserved rhythmic expression in the same homologous organ. This conservation of rhythmic expression is tissue-specific. For instance, within mouse-baboon orthologs which are rhythmic in baboon liver, 45% are detected rhythmic in mouse liver. This supports that rhythmicity at the mRNA level plays a functional role, subject to purifying selection. Furthermore, we find evidence that rhythmic orthologs are genes whose cost of expression, from gene to protein level, is higher than that of other genes. The rhythmic expression of these genes might be an evolutionary advantage, allowing a widespread reduction of costs of protein production.

ABSTRACT. The recognition that accrual of genomic mutations is conducive to carcinogenesis has focused most cancer research on the promotion of oncogenic changes via mutagenesis. Much less attention has been paid to the specific determinants of cancer cell selection. At the most fundamental level, however, transformed cell phenotypes are unlikely to result in successful cancer establishment if not selected. Mutagenesis simply provides the genetic diversity that affords new selectable cell fitness advantages.

All cardinal features of cancer exhibit increased catabolic and/or anabolic support requirements. Cancer cells also encounter widely varying environmental conditions during carcinogenesis, cancer growth, and metastasis. As such, dysregulated intermediary metabolism – an established hallmark of cancer – is uniquely suited to serve as a major basis for selection.

Intermediary metabolism is neither a fixed property nor a unitary entity, and metabolic fitness can vary widely with changing substrate availability or conditions. As such, fixed metabolic phenotypes could disfavor the selection of cancer cells unable to optimally utilize available resources to meet prevailing cellular demands under changing heterotrophic conditions. In contrast, the ability to alter the metabolic gestalt in response to environmental changes could favor selection based on adaptive metabolic fitness.

Metabolic responses can be either adaptive or maladaptive across the spectrum of both physiological and non-physiological environmental conditions. Transformed cells with the intrinsic phenotypic plasticity to adapt to broad variability in both the types and amounts of available nutrients may be better suited for survival than cells with any particular fixed metabolic characteristic. The ability to adapt to mesotrophic or oligotrophic conditions may also obviate metabolic bottlenecks and provide competitive growth advantages that promote selection. A corollary of such relationships would assert similar selection advantages during rapid clonal expansion, tissue invasion, and metastasis. Such behavior could also help explain observed deviations from modeled tumor development and spread.

ABSTRACT. Many studies have found an association between child's health and maternal stress during pregnancy, such as domestic violence. Identifying these cases can be difficult and biomarkers of chronic stress, such as capillary cortisol, may be helpful. In a population-based birth cohort from the outskirts of the city of São Paulo, it was found a causal association between stress in pregnancy (violence and capillary cortisol levels) and intrauterine growth restriction (IUGR) in female neonates and cognitive delay in male infants of 6 months of age (n=183). In order to understand if there are selective pressures favoring such sexually dimorphic response, as well as which they could be, we revisited great evolutionary processes that determine and condition sexual reproduction. A particularly important concept approached here is the dichotomy between r and K reproduction strategies, the first one being more interested in quantity in the offspring, whilst the second one values quality. We hypothesize, in accordance with previous findings, that the observed dimorphisms may have an adaptive value in contexts of environmental instability, along with a higher inclination towards polyandrogyny in its mating system, and an increased competitivity amongst males in order to gain access to fertile females. Our hypotheses imply the existence of polymorphisms that are maintained in the population through variability generating mechanisms, which accompany female choice. This can entail important consequences for public health, since low birth weight has been associated with early puberty, higher fertility rate, less paternal involvement in parental care, maternal withdrawal from work and, eventually, scarce human capital in adulthood. Finally, we suggest ways to test some assumptions presented in our hypotheses by comparing evolutionary rates in genes involved in the determination of social grouping, affectivity, stress signaling through the placenta and mutation rates.

ABSTRACT. Menopause is the permanent cessation of menstruation and/or the irreversible loss of the ability to produce offspring due to the cessation of ovarian follicular activity. Menopause results from a particular pattern of oogenesis. Mammals and birds generate hundreds, thousands or, in the case of humans, millions of eggs early in the lifespan, and oogenesis is complete before, or just after, birth or hatching. In these species, there is a gradual loss of oocytes through ovulation and follicular atresia across the lifespan. With the exception of humans and various species of whales, most females die before the complete exhaustion of ovarian follicles. However, menopause has been observed among some individuals in dozens of mammalian species. Menopause and post-reproductive life can only occur in species that end the production of gametes. Fish, amphibians, and most reptiles cannot demonstrate a menopause because oogenesis continues across life. Monotremes share the same pattern of oogenesis and oocyte loss as demonstrated in all other mammals. Therefore, it appears that the shift from a fish-like pattern of continuous oogenesis to a mammalian and bird-like pattern of abbreviated oogenesis occurred within the reptiles, but evidence for this has been difficult to find. This presentation will present evidence that the capacity for menopause and post-reproductive life evolved more than 200 mya. One reptile group in particular provides clues to explain when and why the female (but not male) pattern of gametogenesis changed. From this phylogenetic perspective, human menopause and post-reproductive life are byproducts of this much earlier change from one stable pattern of continuous oogenesis to a new stable pattern of constrained oogenesis and oocyte loss. The new pattern brought about the loss of ovarian follicular activity with age, resulting in menopause.

ABSTRACT. The MLD 46 Australopithecus africanus proximal femur from Makapansgat, South Africa, represents the earliest known case of hip osteoarthritis in the human fossil record. Dated to 2.6 million years ago, it long predates the second oldest fossil with hip osteoarthritis a 50-000-year-old Neanderthal. Based on its large size, MLD 46 probably belonged to a male individual, while the closed epiphyses and the generally low life expectancy in the Plio-Pleistocene indicate a young adult age. MLD 46 shows extensive marginal and medial osteophytes, without collapse of the head. This suggests that the severe hip osteoarthritis resulted from acetabular protrusion, which in young adults is often associated with bone marrow expansion due to haemoglobinopathies such as sickle-cell disease and thalassemia. A large piece of bone was flaked off from the femoral head anteriorly, revealing various subchondral cysts and a large cone-shaped sclerotic zone in the medial sector of the head. This sclerotic zone was confirmed by micro-CT examination. Its differential diagnosis includes a bone island, a tumour metastasis, or, most likely, osteonecrosis. Osteonecrosis represents a common complication of sickle-cell disease. Other aetiologies of osteonecrosis including corticosteroid medication and alcoholism are less likely in prehistoric times. In addition, the micro-CT images revealed clogging of various fine branches of the medial femoral circumflex artery at the tip of the osteonecrotic area. Osteonecrosis due to infarction of the proximal femoral epiphysis is characteristic of sickle-cell disease. Because sickle-cell disease offers protection against malaria tropica, the earliest human ancestors must already have evolved adaptations against Plasmodium falciparum infections. So far, malaria tropica was thought to have originated in humans when forests were destroyed at the agricultural transition, thereby facilitating a cross-species transmission of Plasmodium parasites from gorillas. Yet, our findings suggest that the origin of malaria dates back to the earliest times of human evolution.

ABSTRACT. The dissociation between the evolutionary adaptation of the human masticatory apparatus and the actual functional needs in modern societies has been proposed as a major factor for increased prevalence of malocclusion and retrognathism. The role of deviating occlusal patterns in the development of temporomandibular disorders (TMDs) is controversial. TMDs likely originate from multiple etiological factors such as occlusion, parafunction, emotional stress, and trauma. Numerous dental studies have tried to test whether there exists a quantifiable relationship between the morphology of the masticatory structures and TMD. These works are heterogeneous and deliver contrasting outcomes, hampering a clear interpretation of the clinical literature. In order to decipher the signal stemming from the evidence-based literature, we performed a meta-analysis of the available clinical literature on occlusion and TMD, considering articles in which patients are thoroughly clinically examined. We excluded studies focusing on children, senile or edentulous individuals, or applying interventional approaches (e.g., orthodontic and prosthetic). We analysed a total of 43 articles out of 201 screened, considering a total of 61 occlusal features relative to the different TMD diagnoses (except for headache aggravated by mastication). Studies using international guidelines for TMD diagnosis were analysed separately from those using sets of signs and symptoms. Our analyses revealed a significant association of the considered occlusal features with TMD in about 30% of the cases. These included sagittal deviations from dental and skeletal class I, posterior open bite, and alteration of jaw dynamics caused by medio- and laterotrusive interferences. We found that articles applying international guidelines for TMD diagnosis were less heterogeneous than those using sets of signs and symptoms. Our outcomes lay the bases for future research investigating the influence of the skeletal and occlusal form on TMD. Understanding this relationship will fundamentally change treatment planning in many clinical settings.

ABSTRACT. The steady rise in global Caesarean rates presents a mounting challenge given the associated health risks and high costs. Here we utilize a Centers for Disease Control and Prevention vital statistic public dataset with detailed accounts surrounding the total live births recorded for the United States in 2017 (n=3,864,754). The data include variables about each parent, maternal prenatal care/medical history and information about the fetus and the birth circumstances. Caesarean sections accounted for 32% of all births in this sample, which exceeds the WHO’s recommendation of a 10-15% section ratio. Therefore, this dataset provides an opportunity to explore the role of maternal phenotypic and socioeconomic variables in assessing Caesarean risk in a population with elevated rates. We explore these predictor variables via machine learning (ML) algorithms due to their efficient application to large datasets.

We used a binary decision tree intended for multiclass classification to train a model to predict vaginal versus Caesarean delivery outcomes. Our birth classification model produced accuracy recalls of over 82% and a precision rate of 93%. Increased Caesarean risk was associated with the time of day, previous Caesarean sections, fetal presentation at birth, and pregnancy with multiples. These results corroborate known predictor variables and correspond with those of a pilot birth classification ML study. Yet, our integration of significantly more data points and different variables provide additional insights into individual predictor influence. Specifically, depending on the percentage of data included in model training, predictor importance differed notably, thereby suggesting that sample size may explain correlations promoted in previous studies. This includes the role of maternal height and education level, which diminished in contribution once larger training samples and more variables were utilized in our analyses. This study demonstrates that models trained via supervised learning offer novel predictive potential for Caesarean section risk assessment.

ABSTRACT. Objectives. The compensatory prophylaxis hypothesis (CPH) proposes that evolved psychological mechanisms enhance the avoidance of potential contaminants during periods of reproductive immunomodulation (such as luteal phase of menstrual cycle) in order to decrease a chance of infection. Meat has been one of the primary sources of foodborne pathogens throughout human evolutionary history, as animals carry pathogenic endosymbionts and parasites, and many microbes proliferate on meat. Therefore, the aim of the study was to analyze differences in meat consumption among healthy, regularly menstruating women. Method. The participants of our pilot study were 34 women aged 18-45. Participants were asked to complete four daily surveys: 1) in the follicular phase on days 3rd and 8th of the cycle, 2) in the luteal phase on days 18th and 23rd. Survey items included questions about the number and size of servings of specific types of meat eaten. Women were also asked to conduct ovulation-detection LH tests from day 10 to 20 of their cycles (counting from the first day of menstrual bleeding) or until a test indicated an ovulation. Results. Women consumed less meat per day in the luteal phase than during the follicular phase (198 grams vs. 244 grams, respectively), but this difference was not statistically significant (p=0.21). Conclusions. Results of the study did not prove any differences in meat consumption among follicular and luteal phase, which is consistent with findings of some previous studies in that field. The meat-borne pathogens widely differ in time of their incubation and, therefore, cyclic alterations in meat consumption might not provide protection from meat-borne infections. Thus, it is possible that alterations in prophylactic behaviors are not related to dietary exposure to pathogens.

ABSTRACT. There is scarce evidence of leprosy and tuberculosis co-occurrence in past human populations and two long-debated hypotheses regarding their co-evolution exist: cross-immunity versus co-infection. This study presents new palaeopathological evidence, namely periosteal new bone formation (PNBF) on the visceral surface of ribs – a proxy to pulmonary pathological conditions, including tuberculosis infection –, in two medieval/modern (13th-17th centuries) cemeteries, from Odense, Denmark. The palaeoepidemiological importance of these skeletal lesions for the understanding of the co-evolution of leprosy and tuberculosis is discussed. We analysed 292 human skeletons – 235 adults from both sexes and 57 non-adults – housed at the University of Southern Denmark (ADBOU), namely: 191 from the St. Jørgen’s leprosarium cemetery [SJG] and 101 from the Blackfriars monastery cemetery [BFM]. Ageing and sexing of skeletons, and macroscopic observation of bones followed standard bioarchaeolological methods. PNBF on the visceral surface or ribs was found in 5.8% (10/173) and 7.3% (7/96) of the skeletons with well preserved ribs from SJG and BFM, respectively (OR=1.282; IC95%: 0.472-3.484). Few of the 4150 ribs observed (59.2% of the total 7008 expected) were affected: 0.9% (22/2504) for SJG and 1.5% (24/1646) for BFM (OR=1.669; IC95%: 0.933-2.987). None of these proportions differed significantly between cemeteries (p>0.05). These findings suggest a low prevalence of pulmonary tuberculosis in the medieval/modern population of Odense. PNBF on ribs was found both in skeletons with (8.1%) and without (5.6%) leprosy related bone lesions (p=0.64), challenging the assumption of a differential mortality in leprosy patients due to pulmonary tuberculosis. The (dis)advantages of palaeopathological approaches to understand leprosy and tuberculosis co-evolution in past human populations will be addressed. Funding: This research was financed by national (POPH – Programa Operacional Potencial Humano) and European (European Social Fund) funds through the FCT – Fundação para a Ciência e Tecnologia: project references UID/ANT/00283/2019 and IF/00186/2014.

ABSTRACT. Evolutionary perspectives on disease first began to be formally introduced in courses in the 1990s, with the publication of Why We Get Sick (Nesse and Williams, 1994), although medical anthropologists have been taking a biocultural approach towards studying health since at least the 1960s (medanthro.net) and biological anthropologists formalized paleopathology as a field in 1973 (paleopathology-association.wildapricot.org). The author began teaching an undergraduate course, Humans, Disease, and Death (HDD), that included foci on evolutionary medicine, paleopathology, and demography in 2002. That course has evolved into two courses that have been taught almost continuously in three different institutions. These courses are now offered at undergraduate and graduate levels, and serve as electives for students in anthropology, biology, public health, and nutrition programs. The HDD course now uses the principles of evolutionary medicine (Gluckman, Beedle, and Hanson, 2016) and anthropological perspectives to study genetic, infectious, and chronic diseases. The emphasis on evidence of disease in the past as well as the past’s influence on modern health, is inherently anthropological - holistic, cross-cultural, evolutionary, and ecological. In 2013, another descendent course emerged to fill a niche of student and faculty interest in Food and Human Evolution (FHE), concentrating on the role that nutrition and cooking have played in the evolution of modern humans. FHE uses the interaction between culture and biology to examine the role diet plays in adaptation, fitness, and health. As a part of George Mason’s University’s focus on undergraduate research, both are taught as “Inquiry” courses, actively involving students in examining primary literature, conducting data analysis, and giving presentations. Assessment shows that students successfully identify major concepts, are confident in their research skills, and have positive attitudes and opinions about the value of science.

ABSTRACT. In pathogenic bacteria surface pili or fimbriae are crucial virulence factors that mediate attachment and infection of host epithelial cells. Among the different fimbrae produced by gram-negative Bacteria, the chaperon-usher (CU) are among the most well studied, in particular in Escherichia coli where each strain may harbor up to 16 different CU operons in its genome. These organelles are key targets for the development of vaccines but without a proper understanding of the mechanisms that generate and maintain diversity in this system, the development of effective vaccines may be hindered. In this study, we characterize the CU operons present in E. coli genomes isolated from clinical samples and associate their patterns of evolution to modes of infection. We show a complicate dynamic of fimbriae evolution with events of whole-operon duplication and lateral transfer, and distinct patterns of protein evolution. Some operons are highly conserved within E. coli with genes under purifying selection, while others show a remarkable rate of evolution with main structural genes showing patterns of polymorphism driven by recombination. These results are likely a consequence of ongoing bacterial-host interactions leading to the acquisition of host tissue adaptation.

ABSTRACT. Sons and daughters differently influence maternal physiology in older age. The higher number of sons, but not the number of daughters, may negatively influence maternal health and may be associated with a shorter life span of mothers. Number of sons may also contribute to increased inflammaging, a chronic sub‐clinical systemic inflammatory state. Inflammaging is characterized by elevated levels of serum inflammatory mediators such as C‐reactive protein (CRP). The aim of this study was to determine the impact of number of children, and number of daughters and sons on serum CRP concentration among older women. This study was conducted amongst a rural Polish population. Serum CRP level was measured in 414 women, aged 45-92 (mean 61.8, SD 11.00), who had 4.0 (SD 2.15) children, including 2.1 (SD 1.49) sons and 1.8 (SD 1.43) daughters on average. Since CRP had a positively skewed distribution gamma regression models were used. There was no significant relationship between serum CRP level and the total number of children (β=1.03, p=0.338), after controlling for women’s age. However, serum CRP concentration was positively associated with the number of sons (β=1.13, p=0.027) but not with number of daughters (β=0.98, p=0.670), after adjusting for women’s age. During pregnancy sons are more energetically demanding and can induce an immune-response in the mother against the male-specific transplantation antigen (HY) which may persist for many years. Our results confirm that sons may have more pronounced immunological impact on the mother also in later life. The vast majority of the studies investigating trade-offs between reproduction and women’s health focus only on their lifetime reproductive effort, namely the total number of children born. Here we present another piece of evidence suggesting that number of children of each sex should be taken into account.

ABSTRACT. The causative agent of tuberculosis, M. tuberculosis complex (MTBC) strains has co evolved with the human populations since their migration out of Africa and subsequently with historic human migration events to become a globally successful pathogen. However, during these speciation process distinct lineages expanded globally (i.e. M. tuberculosis) and others like M. africanum (Maf) are restricted to the West African (WA) region with evidence of a reduced disease susceptibility in African people. It is hypothesized that Maf takes over the role as a specialist that is very well adapted to a particular host population and M. tuberculosis as generalists that can successfully transmit between genetically diverse host populations. Less is known how an evolutionary host-pathogen mismatch impacts on the pathobiology and transmissibility of MTBC bacteria. This study evaluate the genetic diversity and pathobiology of Maf-WA compared to other M.tuberculosis clinical isolates in a bovine macrophage model. So far, reproducibility of the infection in the microenvironment of the bovine macrophage was successful as well as different intracellular survival patterns were found. This study not merely set the foundation of a novel infection model but also gives insights to better understanding into overall successfulness of MTBC bacteria along with the evolutionary signatures of disease susceptibility.

ABSTRACT. A much-criticized view in the philosophy of medicine defines a pathological phenotype as one that fails to perform the function that it was selected for by evolution. Here we sidestep issues regarding whether this “selected effects” approach is a useful heuristic for characterizing pathological states and instead consider a more fundamental problem. The evolutionary definition presumes that when a phenotypic trait evolves by natural selection, some activity or activities of that phenotype, in interaction with ancestral environments, explains why ancestors with the phenotype proliferated or persisted. Selected effects accounts have recently been proposed for mental disorders, such as depression and generalized anxiety disorder. Two distinct approaches and seemingly inconsistent conclusions have subsequently emerged. One approach maintains that common mental disorders are objectively dysfunctional in an evolutionary sense and therefore focuses on elucidating the genetic mechanisms which maintain susceptibility. Others have argued that at least some common mental disorders might be developmental mismatches due to phenotypic plasticity and, although genuine disorders, are not dysfunctional from an evolutionary perspective. We introduce the early results from an interdisciplinary project that applies philosophical analysis and quantitative modeling to clarify how phenomena, such as mental disorders, are subject to the selected effects account of dysfunction.

ABSTRACT. Popular maternity simulation manikins used in advanced practice nursing programs replicate a number of pathologies and processes using high-tech programming, but fall short at modeling physiologically normal, low-intervention birth in a naturalistic manner due to the mechanical limitations of the manikins along with the priorities of the designers and manufacturers. While these manikins can simulate postpartum hemorrhage, seizures, shoulder dystocia, and delivery of a cyanotic infant, they cannot be moved into squatting or sitting postures, be shown to walk around in labor, or get into a birth tub filled with water. By emphasizing technology over a full range of postures and labor support strategies, the design of these mannequins reinforces a passive role for laboring bodies and the notion that health care providers are really the ones who deliver babies—in opposition to an evolutionary perspective that emphasizes the human anatomical, physiological, and behavioral adaptations for birth, including the value of a dedicated care provider for physical and emotional support. This failure to model physiologically normal, low-intervention birth scenarios conditions advanced practice nursing students to expect that birth occurs exclusively or by default in the lithotomy position, pointing to a clear need for insights from evolutionary medicine in nursing education.

ABSTRACT. Cholesterol is one of the most important biochemical parameters for humans. A number of recent researches suggest that reverse cholesterol transport (RCT) regulates not only the homeostasis of cellular cholesterol, but also innate immunity. Involvement of cholesterol in the innate immune response is mediated by ATP-transporter ABCA1, regulating RCT. By regulating the content of cholesterol in lipid rafts, it is involved in the activation of TLR, phagocytosis and regulation of apoptosis. ABCG1 plays an important role in atherogenesis. Objective: study the expression of genes ABCA1, ABCG1 in smoking. The analysis was carried out on previously studied data sets (gene sets) derived from Genes Expression Omnibus (GEO). Researching of alveolar macrophages in smokers (sets GSE2125, GSE8823) showed a significant decrease in the expression of genes ABCA1, ABCG1 compared with non-smokers. Researching of monocytes in patients with COPD (set GSE8808) showed a significant decrease in the expression of ABCA1 compared with healthy individuals, which emphasizes changes in the activation of monocytes in peripheral blood. This can serve as a mechanism of trained innate immune response in atherosclerosis in COPD patients. Genes expression in the airway epithelium in smokers showed conflicting results. There were not significant changes in the gene expression of ABCB1, ABCG1 in sets GSE4498, GSE994, GSE11906, though in sets GSE76324, GSE18385, GSE11784 gene expression of АВСА1 increased. Expression of ABCA3 significantly increased in smokers in sets GSE76324, GSE18385, GSE63127, GSE64614, GSE11906, GSE11784. Gene expression in alveolar epithelial type II cells in patients with COPD compared with healthy individuals (set GSE29133) showed a significant decrease in the expression of genes ABCA1, ABCG1. Thus, smoking disrupts the RCT in monocytes, macrophages and respiratory epithelium, which probably serves as a mechanism of progression of local and systemic inflammation through the mechanisms of the innate immune system.

ABSTRACT. The spread and maintenance of multidrug resistance plasmids (MDR) in clinical settings is a challenge to modern medicine and a puzzler to evolutionary biologists. The impact of resistance plasmids on host fitness is often detrimental, but adaptation processes during experimental evolution reduce plasmid cost. Various mechanisms compensate high-cost plasmids by improving and stabilizing host-plasmid relationships. We aimed to describe adaptive routes for a clinical low-cost carbapenemase-encoding plasmid from Klebsiella pneumoniae when introduced into an uropathogenic Escherichia coli isolate. We performed experimental evolution, fitness assays and whole genome sequencing (WGS) to understand compensation of the plasmid cost. After evolution we identified a clone where the cost of carrying a blaVIM-1-encoding plasmid was ameliorated. No mutations were found on the evolved plasmid. A cpdA non-synonymous mutation previously associated with media adaptation was identified in the chromosome. This adapted host also reduced the cost of an unrelated blaNDM-1-encoding, clinical plasmid. Three chromosomal target genes for adaptive changes, cpdA, arcA and crp, were identified at the population level. This was true for evolved plasmid-carrying, as well as evolved plasmid-free populations suggesting that these mutations occurred independently of plasmid carriage. Stability of MDR plasmids in new hosts depends on the adaptability of plasmid and host. We show increased fitness effect of a general media adaption on a plasmid-host relationship. The underlying mechanism leading to reduced plasmid cost requires further investigation, since it facilitates the persistence and spread of resistance plasmids.

ABSTRACT. Over 60 years ago, George Williams developed the idea that a major contributor to the evolution of senescence was antagonistic pleiotropy, a genetic mechanism by which alleles that increase early life fitness with deleterious effects in later life could be favored by selection. At the time, the idea was speculative in that no real-world examples of such alleles had been discovered. However, in the past twenty years, molecular biologists investigating mechanisms of aging have uncovered many such genes without generally realizing that they were relevant to a major theory of aging. Here, we present a brief review of specific examples of antagonistic pleiotropy in both wild and laboratory organisms. We find that whenever antagonistic pleiotropy has been searched for in earnest, it has been found. Interestingly, the pleiotropic effects are not always directly in the form of tradeoffs between reproduction and longevity but can include impacts on developmental timing and stress resistance as well. Overall, antagonist pleiotropy is common if not ubiquitous in aging biology with the implication that molecular mechanisms of aging are likely to be widely shared among organisms.

ABSTRACT. Antibiotic resistance is a growing challenge. Resistance can rapidly emerge during treatment, due to the high potential of bacteria for rapid evolutionary adaptation. One approach to sustain the efficacy of antibiotics is to develop treatment strategies that inhibit resistance evolution. This talk will show an example of a new treatment strategy - hysteresis treatments - that inhibits resistance evolution by using available antibiotics in a new way. Hysteresis treatments exploit cellular phenotypic memory, which refers to long-lasting changes in cellular physiology induced by previous antibiotic exposures. Antibiotics can act as signals, and induce specific and long-lasting cellular responses, such as heat-shock response, motility and changes in membrane permeability. Bacterial responses are stabilized across generations and can have pleiotropic effects for treatment with other antibiotics. Cellular memory can harm bacteria, when they are treated with appropriate sequences of antibiotics. Using evolution experiments, mathematical modelling, genomics, and functional genetic analysis, we demonstrate that hysteresis treatments are highly efficient - they cause extinction at sub-MIC concentrations - and inhibit the evolution of resistance. Hysteresis treatments impose specific selective pressure on the bacteria that does not favour resistance mutations, but rather mutations causing cellular ignorance behaviour, or a loss of memory. Cellular hysteresis can be harnessed as a novel principle to optimise antibiotic therapy, in order to achieve both, enhanced bacterial elimination and reduced resistance evolution.

ABSTRACT. The cardiovascular system developed in multicellular organisms about 500 million years ago. Now cardiovascular diseases (CVD) present the most important burden of the non-communicable diseases worldwide. CVD are particularly suited for a holistic approach to health and disease based on our increasingly precise molecular understanding of evolution: genetic causes have been identified, basic mechanisms are elucidated and there are unique opportunities for treatment and prevention. Evolutionary medicine can make major contributions at all levels: research, treatment, prevention. Factors important for health and CVD in addition to our biology can be summarized as environmental (e.g. climate, poverty, hunger, pollution, urbanization, socio-economic factors) and lifestyle (e.g. education, nutrition, physical Activity). Epigenetic effects are increasingly recognized. They all contribute to, or are risk factors for, cardiovascular diseases such as hypertension, obesity, metabolic and kidney diseases, diabetes, heart failure.

This supports the lessons learned from evolution that biology, survival, reproduction, life and death cannot be understood if we do not include and consider the lifestyle and the environment. The 17 Sustainable Development Goals SDGs of the United Nations can be subdivided in exactly these 3 evolutionary categories: biology, environment and lifestyle. SDG 3 “Health and Well-Being for All” and the Action Plan of the World Health Organization (WHO), proclaimed at the World Health Summit 2018 in Berlin, are a milestone in this direction. It must be our collective goal to make a significant contribution. The holistic concept of Evolutionary Medicine can provide orientation for research and translation into better health for all.